Estimation of Genetic Relationships Between Individuals Across Cohorts and Platforms: Application to Childhood HeightReport as inadecuate




Estimation of Genetic Relationships Between Individuals Across Cohorts and Platforms: Application to Childhood Height - Download this document for free, or read online. Document in PDF available to download.

Behavior Genetics

, Volume 45, Issue 5, pp 514–528

First Online: 03 June 2015Received: 18 December 2014Accepted: 20 May 2015DOI: 10.1007-s10519-015-9725-7

Cite this article as: Fedko, I.O., Hottenga, JJ., Medina-Gomez, C. et al. Behav Genet 2015 45: 514. doi:10.1007-s10519-015-9725-7

Abstract

Combining genotype data across cohorts increases power to estimate the heritability due to common single nucleotide polymorphisms SNPs, based on analyzing a Genetic Relationship Matrix GRM. However, the combination of SNP data across multiple cohorts may lead to stratification, when for example, different genotyping platforms are used. In the current study, we address issues of combining SNP data from different cohorts, the Netherlands Twin Register NTR and the Generation R GENR study. Both cohorts include children of Northern European Dutch background N = 3102 + 2826, respectively who were genotyped on different platforms. We explore imputation and phasing as a tool and compare three GRM-building strategies, when data from two cohorts are 1 just combined, 2 pre-combined and cross-platform imputed and 3 cross-platform imputed and post-combined. We test these three strategies with data on childhood height for unrelated individuals N = 3124, average age 6.7 years to explore their effect on SNP-heritability estimates and compare results to those obtained from the independent studies. All combination strategies result in SNP-heritability estimates with a standard error smaller than those of the independent studies. We did not observe significant difference in estimates of SNP-heritability based on various cross-platform imputed GRMs. SNP-heritability of childhood height was on average estimated as 0.50 SE = 0.10. Introducing cohort as a covariate resulted in ≈2 % drop. Principal components PCs adjustment resulted in SNP-heritability estimates of about 0.39 SE = 0.11. Strikingly, we did not find significant difference between cross-platform imputed and combined GRMs. All estimates were significant regardless the use of PCs adjustment. Based on these analyses we conclude that imputation with a reference set helps to increase power to estimate SNP-heritability by combining cohorts of the same ethnicity genotyped on different platforms. However, important factors should be taken into account such as remaining cohort stratification after imputation and-or phenotypic heterogeneity between and within cohorts. Whether one should use imputation, or just combine the genotype data, depends on the number of overlapping SNPs in relation to the total number of genotyped SNPs for both cohorts, and their ability to tag all the genetic variance related to the specific trait of interest.

KeywordsGenotyping platform Heterogeneity Imputation GCTA SNP-heritability Height Edited by Gitta Lubke.

Download fulltext PDF



Author:

Source: https://link.springer.com/







Related documents